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WO2003053945A2 - Nouveaux composes - Google Patents

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Publication number
WO2003053945A2
WO2003053945A2 PCT/GB2002/005812 GB0205812W WO03053945A2 WO 2003053945 A2 WO2003053945 A2 WO 2003053945A2 GB 0205812 W GB0205812 W GB 0205812W WO 03053945 A2 WO03053945 A2 WO 03053945A2
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Prior art keywords
compound
formula
alkyl
pharmaceutically acceptable
alkoxy
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WO2003053945A3 (fr
Inventor
Harshad Kantilal Rami
Mervyn Thompson
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority to EP02788192A priority Critical patent/EP1474403A2/fr
Priority to JP2003554661A priority patent/JP2005516951A/ja
Priority to US10/496,194 priority patent/US20060100202A1/en
Priority to AU2002352476A priority patent/AU2002352476A1/en
Publication of WO2003053945A2 publication Critical patent/WO2003053945A2/fr
Publication of WO2003053945A3 publication Critical patent/WO2003053945A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • This invention relates to novel compounds, especially urea derivatives, having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of various disorders.
  • Vanilloids are a class of natural and synthetic compounds which are characterised by the presence of a vanillyl (3-hydroxy 4-methoxyphenyl) group or a functionally equivalent group. Vanilloid Receptor (VR1), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51 , No. 2.).
  • Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285.
  • vanilloid compounds or vanilloid receptor modulators are capsaicin, namely trans 8-methyl-N-vanillyl-6- nonenamide, isolated from the pepper plant, capsazepine (Tetrahedron, Vol. 53, No. 13, pp. 4791- 4814, 1997) and olvanil - N-(3-methoxy-4-hydroxy- benzyl)oleamide ( J. Med. Chem. 1993, 36, 2595-2604).
  • US Patent Numbers US 3,424,760 and US 3,424,761 both describe a series of 3-Ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacologic activities. These patents specifically disclose the compounds 1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and 1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyI)urea respectively.
  • Co-pending International Patent Application Number PCT/EP02/04802 discloses a series of urea derivatives and their use in the treatment of diseases associated with the activity of the vanilloid receptor.
  • a structurally novel class of compounds has now been found which also possess Vanilloid receptor (VR1 ) antagonist activity.
  • the present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
  • P is phenyl, naphthyl or heterocyclyl
  • R1 is selected from -H, halo, alkyl, alkoxy, cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, -CN, -NO2, -OH, -OCF3, -CF3, -NR 5 R 6 , - S(0) m R 7 , -S(0) 2 NR5R6, -OS(0) 2 R 7 , -OS(0) 2 CF 3 , -0(CH 2 ) X NR 5 R 6 , - C(0)CF 3 , -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, - C(0)(CH 2 ) x OR 7 , -C(0)(CH 2 ) X NR5R6 J -C(0)alkoxy, -C(0)NR 5 R6, - (CH 2 ) x C(0)alkoxy, -(CH
  • X is a bond, C, O or NR a
  • R3 is selected from -H, halo, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, -CN, -NO2, -OH, -OCF3, -CF3, -NR 5 R 6 , - S(0) m R 7 , -S(0) 2 NR 5 R 6 , -OS(0) 2 R 7 , -OS(0) 2 CF 3 , -0(CH 2 ) X NR5R6, - C(O)CF 3 , -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, - C(0)(CH 2 ) x OR 7 , -C(0)(CH 2 ) X NR 5 R6, -C(0)alkoxy, -C(0)NR5R6, .
  • R4 is hydrogen or alkyl
  • R5 and R ⁇ may be the same or different and represent H or alkyl or R5 and R6 together with the atoms to which they are attached form a C 3 .
  • Z is O, S or NR ⁇
  • R 7 is alkyl or aryl
  • R8 is hydrogen, alkyl or aryl; n is 2, 3, 4, 5 or 6;
  • p is O, 1 , 2, 3 or 4;
  • q 0, 1 , 2 or 3;
  • r 0, 1 or 2;
  • x is O, 1 , 2, 3, 4, 5 or 6.
  • P is phenyl, naphthyl, cinnolinyl or isoquinolinyl.
  • P is naphthyl
  • a preferred group is naphth-1-yl.
  • P is phenyl.
  • R 1 is halo, alkyl, alkoxy, -C(0)alkyl, -NO2, -CF3, -CN or - OCF3. More suitably, R 1 is halo, alkyl, -C(0)alkyl or -OCF3. Preferably, R 1 is halo, -C(0)Me or -OCF3.
  • R2 is
  • R 2 is dihydroindolyl, tetrahydroydroquinolinyl or dihydrobenzo[1 ,4]oxazinyl.
  • R 2 is 2,3-dihydroindol-1-yl, 3,4- dihydro-2H-quinolin-1-yl or 2,3-dihydrobenzo[1 ,4]oxazin-4-yl.
  • R 3 is halo, alkyl, alkoxy, -CF3, -CN or aryl. More suitably, R 3 is halo or alkyl. Preferably, R 3 is fluoro or methyl. Most preferably, R 3 is a methyl or fluoro substituted at either the 4- or 5 -position on the dihydroindole ring, a methyl group substituted on the 6-position of the dihydroquinolinyl ring or a methyl group substituted on the 7-position of the dihydrobenzo[1 ,4]oxazinyl ring.
  • R4 is alkyl. Preferably, R4 is methyl.
  • R is alkyl.
  • R 5 is methyl.
  • the groups R ⁇ may be the same or different.
  • p is 1 or 2.
  • the groups R4 may be the same or different.
  • r is 0 or 1.
  • n is 2 or 3. Most preferably, n is 2.
  • q is 1 or 2. Most preferably, q is 1.
  • x is 0.
  • Particularly preferred compounds according to the invention include examples E1 to E58 or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of formula (I) can form salts, especially pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts are those use conventionally in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts.
  • Suitable pharmaceutically acceptable salts include acid addition salts.
  • Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.
  • inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid
  • organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic
  • salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated.
  • This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms.
  • alkyl groups in particular include methyl ("Me”), ethyl (“Et”), n-propyl (“Pr n “), /so-propyl (“Pr'”), n-butyl (“Bun”), sec-butyl (“Bu S “), terf-butyl ("But”), pentyl and hexyl.
  • alkyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C2-6 alkenyl, C ⁇ _Q alkynyl, C ⁇ _ ⁇ alkoxy, aryl and di-C-
  • halo such as fluoro, chloro, bromo
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • alkoxy groups in particular include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, /so-butoxy, sec-butoxy and terf-butoxy.
  • alkoxy groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C- ⁇ s alkyl, C2-6 alkenyl, C3..6 alkynyl, aryl and di-C ⁇ .g alkylamino.
  • halo such as fluoro, chloro, bromo
  • -CN such as fluoro, chloro, bromo
  • -CF3, -OH, -OCF3 C- ⁇ s alkyl
  • C2-6 alkenyl C3..6 alkynyl
  • aryl and di-C ⁇ .g alkylamino.
  • aryl as a group or part of a group refers to a carbocyclic aromatic radical ("Ar”).
  • Ar carbocyclic aromatic radical
  • aryl groups are 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups, especially phenyl (“Ph”), biphenyl and naphthyl, particularly phenyl.
  • halo is used herein to describe, unless otherwise stated, a group selected from fluorine ("fluoro"), chlorine (“chloro”), bromine (“bromo”) or iodine ("iodo").
  • naphthyl is used herein to denote, unless otherwise stated, both naphth-1-yl and naphth-2-yl groups.
  • 'heterocyclyl' is used herein to describe, unless otherwise stated, groups comprising one or more rings which may be saturated, unsaturated or aromatic and which may independently contain one or more heteratoms in each ring.
  • heterocyclyl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H- 1 ,5,2-dithiazinyl, dihydrobenzofuranyl, furanyl, furazanyl, imidazolyl, 1 H- indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinol, is
  • the present invention also provides, in a further aspect, a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which process comprises coupling a compound of formula (II):
  • R 2 and n are as defined in formula (I) and A and B contain the appropriate functional groups which are capable of reacting together to form the urea moiety; and optionally thereafter if appropriate: (i) removing any protecting groups; (ii) forming a pharmaceutically acceptable salt or solvate of the compound so formed.
  • Suitable examples of appropriate A and B groups include:
  • A is NH2 and B is NH2 together with an appropriate urea forming agent.
  • reaction is carried out in an inert solvent such as dichloromethane or acetonitrile.
  • the urea forming agent can be carbonyl diimidazole or phosgene.
  • the reaction may be performed in an inert organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane at ambient or elevated temperature.
  • the reaction is typically performed in the presence of a base such as triethylamine or pyridine.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • Vanilloid receptor antagonist V1
  • V1 Vanilloid receptor antagonist
  • the invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof for use in the treatment or prophylaxis of pain and urinary incontinence.
  • the invention further provides a method of treatment or prophylaxis of the Disorders of the Invention, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral, rectal administration or intravesical adminstration to the bladder and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions, suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt or solvate thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5 and 0.1 to 250 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 1000 mg; and such therapy may extend for a number of weeks or months.
  • the title compound was prepared from 4-fluoroindoline (D8) using the procedure outlined for Description 1 (0.7g, 97%).
  • the compounds of the invention are vanilloid receptor (VR1 ) antagonists and hence have useful pharmaceutical properties.
  • Vanilloid receptor (VR1) antagonist activity can be confirmed and demonstrated for any particular compound by use of conventional methods, for example those disclosed in standard reference texts such as D. Le Bars, M. Gozarin and S. W. Cadden, Pharmacological Reviews, 2001 , 53(4), 597- 652] or such other texts mentioned herein.
  • the screen used for the compounds of this invention was based upon a FLIPR based calcium assay, similar to that described by Smart et al. (British Journal of Pharmacology, 2000, 129, 227-230).
  • Transfected astrocytoma 1321 N1 cells, stably expressing human VR1 were seeded into FLIPR plates at 25,000cells/well (96-well plate) and cultured overnight.
  • the cells were subsequently loaded in medium containing 4 ⁇ M Fluo-3 AM (Molecular Probes) for 2 hours, at room temperature, in the dark. The plates were then washed 4 times with Tyrode containing 1.5mM calcium, without probenecid. The cells were pre-incubated with compound or buffer control at room temperature for 30 minutes. Capsaicin (Sigma) was then added to the cells. Compounds having antagonist activity against the human VR1 were identified by detecting differences in fluorescence when measured after capsaicin addition, compared with no compound buffer controls. Thus, for example, in the buffer control capsaicin addition results in an increase in intracellular calcium concentration resulting in fluorescence.
  • Fluo-3 AM Molecular Probes
  • a compound having antagonist activity blocks the capsaicin binding to the receptor, there is no signalling and therefore no increase in intracellular calcium levels and consequently lower fluorescence.
  • pKb values are generated from the IC50 values using the Cheng-Prusoff equation. All compounds tested by the above methodology had pKb > 6, preferred compounds [Examples 1 , 3, 10, 11 , 12, 14-17, 19, 20-25, 27-33, 37, 39-47, 49, 50, 52, 54, 56, 57 and 58] had a pKb > 7.0.

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  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Nutrition Science (AREA)
  • Otolaryngology (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne des composés de formule générale (I) ou un sel ou un solvate pharmaceutiquement acceptable de ceux-ci, dans laquelle R1, R2, P, p et n ont la signification indiquée dans la description. L'invention concerne également un procédé de préparation desdits composés, une composition pharmaceutique les contenant, ainsi que l'utilisation desdits composés à des fins médicales.
PCT/GB2002/005812 2001-12-20 2002-12-19 Nouveaux composes Ceased WO2003053945A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP02788192A EP1474403A2 (fr) 2001-12-20 2002-12-19 Derives d'uree et leur utilisation comme antagonistes des recepteurs vanilloides
JP2003554661A JP2005516951A (ja) 2001-12-20 2002-12-19 尿素誘導体およびバニロイド受容体アンタゴニストとしてのその使用
US10/496,194 US20060100202A1 (en) 2001-12-20 2002-12-19 Novel compounds
AU2002352476A AU2002352476A1 (en) 2001-12-20 2002-12-19 Urea derivatives and their use as vanilloid receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0130550.7A GB0130550D0 (en) 2001-12-20 2001-12-20 Novel compounds
GB0130550.7 2001-12-20

Publications (2)

Publication Number Publication Date
WO2003053945A2 true WO2003053945A2 (fr) 2003-07-03
WO2003053945A3 WO2003053945A3 (fr) 2004-03-11

Family

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PCT/GB2002/005812 Ceased WO2003053945A2 (fr) 2001-12-20 2002-12-19 Nouveaux composes

Country Status (6)

Country Link
US (1) US20060100202A1 (fr)
EP (1) EP1474403A2 (fr)
JP (1) JP2005516951A (fr)
AU (1) AU2002352476A1 (fr)
GB (1) GB0130550D0 (fr)
WO (1) WO2003053945A2 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
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WO2004007459A3 (fr) * 2002-07-12 2004-03-18 Janssen Pharmaceutica Nv Modulateurs ureiques du recepteur vanilloide vr1 derives du naphtol, de la quinoline et de l'isoquinoline
WO2004024154A1 (fr) * 2002-09-12 2004-03-25 Glaxo Group Limited Utilisation d'un antagoniste du recepteur vanilloide pour traiter la douleur
EP1493438A1 (fr) * 2003-07-03 2005-01-05 Bayer HealthCare AG Inhibiteurs du recepteur vanilloide (VR1) dans le traitement de la douleur associée au VIH
WO2005016915A1 (fr) 2003-08-14 2005-02-24 Glaxo Group Limited Derives carboxamides de piperidine/cyclohexane destines a etre utilises comme modulateurs du recepteur vanilloide
WO2005016922A1 (fr) * 2003-08-14 2005-02-24 Glaxo Group Limited Derives carbazole-2-carboxamides possedant une activite antagoniste du recepteur vanilloide
WO2006006741A1 (fr) * 2004-07-15 2006-01-19 Japan Tobacco Inc. Composé benzamide fusionné et inhibiteur d'activité récepteur vanilloïde 1 (vr1)
JP2007501246A (ja) * 2003-02-11 2007-01-25 アボット・ラボラトリーズ バニロイド受容体サブタイプ１（ｖｒ１）受容体を阻害する縮合アザ二環式化合物
WO2007074916A1 (fr) 2005-12-28 2007-07-05 Japan Tobacco Inc. Compose de 3,4-dihydrobenzoxazine et inhibiteur de l'activite du recepteur de vanilloide de type 1 (vr1)
US7618993B2 (en) 2005-12-23 2009-11-17 Astrazeneca Ab Compounds
US7645784B2 (en) 2003-05-16 2010-01-12 Astrazeneca Ab Benzimidazole derivatives
US7683076B2 (en) 2003-11-08 2010-03-23 Bayer Schering Pharma Aktiengesellschaft Tetrahydro-quinolinylurea derivatives
US7728005B2 (en) 2003-10-14 2010-06-01 Ajinomoto Co., Inc. Ether derivative
US7767705B2 (en) 2006-08-25 2010-08-03 Abbott Laboratories Compounds that inhibit TRPV1 and uses thereof
US7906508B2 (en) 2005-12-28 2011-03-15 Japan Tobacco Inc. 3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (VRI) activity
US7906654B2 (en) 2006-08-11 2011-03-15 Astrazeneca Ab Benzimidazole derivatives
US8088826B2 (en) 2002-12-06 2012-01-03 Xention Limited Tetrahydro-naphthalene derivatives
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen

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ES2319886T3 (es) * 2002-02-20 2009-05-14 Abbott Laboratories Compuestos azabiciclicos condensados que inhiben el sutipo 1 del receptor valinoide (vr1).
US20060035939A1 (en) * 2004-07-14 2006-02-16 Japan Tobacco Inc. 3-Aminobenzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity
RU2387640C1 (ru) * 2008-09-18 2010-04-27 Учреждение Российской академии наук Институт элементоорганических соединений имени А.Н. Несмеянова РАН (ИНЭОС РАН) Способ получения 1-(аминоалкил)индолинов
ES2537407T3 (es) * 2009-05-01 2015-06-08 Henkel US IP LLC Acelerantes del curado para composiciones curables anaerobias

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US3247211A (en) * 1963-01-18 1966-04-19 Eastman Kodak Co Cyanomethylidene quinolines
US5840720A (en) * 1995-10-23 1998-11-24 Tong-Ho Lin 4-O and 5-aminomethylation of synthetic capsaicin derivatives, a new discovery of capsaicin antagonist
WO1998020867A1 (fr) * 1996-11-15 1998-05-22 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Compositions pharmaceutiques contenant des agonistes vanilloides en combinaison avec des antagonistes vanilloides

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004007459A3 (fr) * 2002-07-12 2004-03-18 Janssen Pharmaceutica Nv Modulateurs ureiques du recepteur vanilloide vr1 derives du naphtol, de la quinoline et de l'isoquinoline
WO2004024154A1 (fr) * 2002-09-12 2004-03-25 Glaxo Group Limited Utilisation d'un antagoniste du recepteur vanilloide pour traiter la douleur
US8173841B2 (en) 2002-12-06 2012-05-08 Xention Limited Tetrahydro-naphthalene derivatives
US8088826B2 (en) 2002-12-06 2012-01-03 Xention Limited Tetrahydro-naphthalene derivatives
JP2007501246A (ja) * 2003-02-11 2007-01-25 アボット・ラボラトリーズ バニロイド受容体サブタイプ１（ｖｒ１）受容体を阻害する縮合アザ二環式化合物
US7645784B2 (en) 2003-05-16 2010-01-12 Astrazeneca Ab Benzimidazole derivatives
EP1493438A1 (fr) * 2003-07-03 2005-01-05 Bayer HealthCare AG Inhibiteurs du recepteur vanilloide (VR1) dans le traitement de la douleur associée au VIH
WO2005002551A3 (fr) * 2003-07-03 2005-10-06 Bayer Healthcare Ag Inhibiteurs de recepteur vanilloide pour le traitement d'etats de douleurs provoques par le virus de l'immunodeficience humaine (vih)
WO2005016915A1 (fr) 2003-08-14 2005-02-24 Glaxo Group Limited Derives carboxamides de piperidine/cyclohexane destines a etre utilises comme modulateurs du recepteur vanilloide
WO2005016922A1 (fr) * 2003-08-14 2005-02-24 Glaxo Group Limited Derives carbazole-2-carboxamides possedant une activite antagoniste du recepteur vanilloide
US7728005B2 (en) 2003-10-14 2010-06-01 Ajinomoto Co., Inc. Ether derivative
US7683076B2 (en) 2003-11-08 2010-03-23 Bayer Schering Pharma Aktiengesellschaft Tetrahydro-quinolinylurea derivatives
WO2006006741A1 (fr) * 2004-07-15 2006-01-19 Japan Tobacco Inc. Composé benzamide fusionné et inhibiteur d'activité récepteur vanilloïde 1 (vr1)
US8008292B2 (en) 2004-07-15 2011-08-30 Japan Tobacco Inc. Condensed benzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity
AU2005260821B2 (en) * 2004-07-15 2010-02-18 Japan Tobacco Inc. Fused benzamide compound and vanilloid receptor 1 (VR1) activity inhibitor
EP2314585A1 (fr) 2004-07-15 2011-04-27 Japan Tobacco, Inc. Composés benzamide fusionnés en tant qu'inhibiteurs de l'activité du récepteur vanilloid sous-type 1 (VR1)
US8168668B2 (en) 2005-12-23 2012-05-01 Astrazeneca Ab Compounds
US7618993B2 (en) 2005-12-23 2009-11-17 Astrazeneca Ab Compounds
WO2007074916A1 (fr) 2005-12-28 2007-07-05 Japan Tobacco Inc. Compose de 3,4-dihydrobenzoxazine et inhibiteur de l'activite du recepteur de vanilloide de type 1 (vr1)
US7906508B2 (en) 2005-12-28 2011-03-15 Japan Tobacco Inc. 3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (VRI) activity
US7906654B2 (en) 2006-08-11 2011-03-15 Astrazeneca Ab Benzimidazole derivatives
US8093402B2 (en) 2006-08-11 2012-01-10 Astrazeneca Ab Benzimidazole derivatives
US7767705B2 (en) 2006-08-25 2010-08-03 Abbott Laboratories Compounds that inhibit TRPV1 and uses thereof
US8815930B2 (en) 2006-08-25 2014-08-26 Abbvie Inc. Compounds that inhibit TRPV1 and uses thereof
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen

Also Published As

Publication number Publication date
AU2002352476A1 (en) 2003-07-09
US20060100202A1 (en) 2006-05-11
WO2003053945A3 (fr) 2004-03-11
GB0130550D0 (en) 2002-02-06
JP2005516951A (ja) 2005-06-09
AU2002352476A8 (en) 2003-07-09
EP1474403A2 (fr) 2004-11-10

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